文章：

脂肪酸合酶和脂肪生成表型在癌症发病中的作用

Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis

原文发布日期：2007-10-01

DOI: 10.1038/nrc2222

类型: Review Article

开放获取: 否

要点：

1. A wide variety of tumours and their precursor lesions undergo exacerbated de novo biogenesis of fatty acids (FAs) irrespective of the levels of circulating lipids. Neoplastic lipogenesis is reflected by significantly increased activity and coordinate expression of several lipogenic enzymes in tumour cells. Upregulation of fatty acid synthase (FASN), the key metabolic multi-enzyme that is responsible for the terminal catalytic step in FA synthesis, represents a nearly-universal phenotypic alteration in most human malignancies.
2. Although the same disturbances in signalling pathways responsible for oncogenic transformation can contribute to increased lipogenesis in tumours, FASN hyperactivity and overexpression is not only a secondary phenomenon that results from the induction of other pathways during carcinogenesis. Rather, it is directly selected for because it provides a growth and/or survival advantage achieved through multiple mechanisms.
3. Early upregulation of FASN in precursor lesions might represent an obligatory metabolic acquisition in response to the microenvironment of pre-invasive lesions (that is, poor oxygenation and high acidity, and/or lack of nutrients), which continue to occur in invasive and/or metastatic stages. The functional and temporal linkage of the 'glycolytic-switch' and the FASN-related lipogenic phenotype may represent co-evolved essential components of the malignant phenotype and, therefore, hallmarks of invasive cancers.
4. Both the persistent prevalence of the exacerbated de novo FA biosynthesis in primary and metastatic malignancy and the existence of bi-directional linkages of FASN with cancer-controlling networks (such as oestrogen receptor and ERBB2), strongly suggest that FASN can work as a previously unrecognized metabolic intermediate of oncogenesis linking energy, anabolism and malignant transformation.
5. As exacerbated lipogenesis emerges early in carcinogenesis, it might represent an exploitable target in cancer prevention by retarding the progression of pre-malignant lesions. At later stages, a more complete understanding of the molecular and physiological consequences of its specific inhibition might lead to targeted therapies for the treatment of advanced or metastatic carcinomas.

要点翻译：

1. 多种肿瘤及其前驱病变均会经历加剧的脂肪酸从头合成，这一过程与循环脂质水平无关。肿瘤细胞的脂质生成特征表现为多种脂生成酶的活性和协调表达显著增强。脂肪酸合酶作为负责脂肪酸合成最终催化步骤的关键代谢多酶，其上调现象在大多数人类恶性肿瘤中几乎可被视为一种普适性表型改变。
2. 尽管导致癌变的信号通路紊乱同样会促进肿瘤中脂质生成的增加，但FASN的过度活化和过度表达并不仅仅是癌变过程中其他通路诱导产生的次要现象。实际上，这种变化是通过多重机制获得生长/生存优势后被直接选择的结果。
3. FASN在前驱病变中的早期上调可能是应对浸润前病变微环境（即低氧、高酸和/或营养缺乏）的必然代谢适应，这种微环境在浸润和/或转移阶段持续存在。"糖酵解转换"与FASN相关脂生成表型在功能和时间上的关联，可能代表了恶性表型中共同进化的基本组成部分，因而成为浸润性癌症的标志特征。
4. 原发性及转移性恶性肿瘤中持续存在的加剧脂肪酸从头生物合成，以及FASN与癌症调控网络（如雌激素受体和ERBB2）之间双向联系的存在，共同强烈提示FASN可能作为先前未被认识的致癌作用代谢中间体，连接着能量代谢、合成代谢与恶性转化。
5. 由于加剧的脂质生成在癌变早期即已出现，它可能成为癌症预防中具有开发价值的靶点，通过延缓癌前病变的进展发挥作用。在疾病后期阶段，更全面理解其特异性抑制带来的分子与生理效应，或能为晚期或转移性癌的靶向治疗开辟新途径。

英文摘要：

There is a renewed interest in the ultimate role of fatty acid synthase (FASN) — a key lipogenic enzyme catalysing the terminal steps in the de novo biogenesis of fatty acids — in cancer pathogenesis. Tumour-associated FASN, by conferring growth and survival advantages rather than functioning as an anabolic energy-storage pathway, appears to necessarily accompany the natural history of most human cancers. A recent identification of cross-talk between FASN and well-established cancer-controlling networks begins to delineate the oncogenic nature of FASN-driven lipogenesis. FASN, a nearly-universal druggable target in many human carcinomas and their precursor lesions, offers new therapeutic opportunities for metabolically treating and preventing cancer.

摘要翻译： 

人们对脂肪酸合酶（FASN）在癌症发病中的终极作用重新产生了兴趣。FASN 是一种关键的脂肪生成酶，催化脂肪酸从头生物合成的最后步骤。肿瘤相关的 FASN 并非作为储存能量的合成代谢途径，而是通过赋予肿瘤细胞生长和生存优势，似乎必然伴随大多数人类癌症的自然进程。近期发现的 FASN 与已确立的癌症调控网络之间的交叉对话，开始勾勒出 FASN 驱动的脂肪生成在致癌过程中的本质。FASN 是许多人类癌及其癌前病变中几乎普遍存在的可药物靶点，为代谢性治疗和预防癌症提供了新的治疗机会。

原文链接：

Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis